A genome-wide library of MADM mice for single-cell genetic mosaic analysis
Ximena Contreras, Nicole Amberg, Amarbayasgalan Davaatseren, Andi H. Hansen, Johanna Sonntag, Lill Andersen, Tina Bernthaler, Carmen Streicher, Anna Heger, Randy L. Johnson, Lindsay A. Schwarz, Liqun Luo, Thomas Rülicke, Simon Hippenmeyer
Abstract
Mosaic analysis with double markers (MADM) offers one approach to visualize and concomitantly manipulate genetically defined cells in mice with single-cell resolution. MADM applications include the analysis of lineage, single-cell morphology and physiology, genomic imprinting phenotypes, and dissection of cell-autonomous gene functions in vivo in health and disease. Yet, MADM can only be applied to <25% of all mouse genes on select chromosomes to date. To overcome this limitation, we generate transgenic mice with knocked-in MADM cassettes near the centromeres of all 19 autosomes and validate their use across organs. With this resource, >96% of the entire mouse genome can now be subjected to single-cell genetic mosaic analysis. Beyond a proof of principle, we apply our MADM library to systematically trace sister chromatid segregation in distinct mitotic cell lineages. We find striking chromosome-specific biases in segregation patterns, reflecting a putative mechanism for the asymmetric segregation of genetic determinants in somatic stem cell division.